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An Algal Nucleus-encoded Subunit of Mitochondrial ATP Synthase Rescues a Defect in the Analogous Human Mitochondrial-encoded Subunit (Ojaimi et al., 2001)

Here, it is shown that essential mitochondrial genes can be nucleus-encoded (Chlamydomonas), in this case the subunit ATPase6. The gene shows eukaryotic characteristics including introns and targeting sequences. The algal gene is even functional in mammalian cells.

From the abstract: Unlike most organisms, the mitochondrial DNA (mtDNA) of Chlamydomonas reinhardtii, a green alga, does not encode subunit 6 of F0F1-ATP synthase. We hypothesized that C. reinhardtii ATPase 6 is nucleus encoded and identified cDNAs and a single-copy nuclear gene specifying this subunit (CrATP6, with eight exons, four of which encode a mitochondrial targeting signal). Although the algal and human ATP6 genes are in different subcellular compartments and the encoded polypeptides are highly diverged, their secondary structures are remarkably similar. When CrATP6 was expressed in human cells, a significant amount of the precursor polypeptide was targeted to mitochondria, the mitochondrial targeting signal was cleaved within the organelle, and the mature polypeptide was assembled into human ATP synthase. In spite of the evolutionary distance between algae and mammals, C. reinhardtii ATPase 6 functioned in human cells, because deficiencies in both cell viability and ATP synthesis in transmitochondrial cell lines harboring a pathogenic mutation in the human mtDNA-encoded ATP6 gene were overcome by expression of CrATP6.

It looks like no mitochondrial gene is essential for mitochondrion function and they can all be nuclear-encoded. The hydrophobicity problem could have been the main driver for transfer to the mitochondria from the nucleus.

With but few exceptions, a “canonical” set of mtDNA-encoded proteins, typically six subunits of NADH dehydrogenase ubiquinone oxidoreductase, the cytochrome b subunit of ubiquinone-cytochrome c oxidoreductase, three subunits of cytochrome c oxidase, and two subunits of ATP synthase, is remarkably conserved among all species examined, ranging from the protist Reclinomonus americana to mammals. Although the reason for this conservation has been the subject of speculation, the most widely held view is that these proteins are so hydrophobic that they are unable to be imported from the cytoplasm, and therefore this set was constrained by evolutionary pressure to remain in the mitochondrial genome (Claros et al., 1995 , 1996 ; Perez-Martinez et al., 2000 , 2001 ).

However, the rules determining which hydrophobic protein genes are retained in the mtDNA are not hard and fast. For example, the mtDNA of the yeasts S. cerevisiae and Schizosaccharomyces pombe contain the ATP9 gene, which encodes subunit c of ATP synthase, whereas subunit c is nucleus encoded in mammals. Even more striking has been the finding that some organisms among the algae, ciliates, apicomplexans, and flowering plants lack mtDNA-encoded COX II, COX III, and/or ATP6, all highly hydrophobic proteins. Because these three subunits are necessary for the functioning of COX and ATP synthase, respectively, it is almost certain that these genes have been transferred to the nuclear DNA in these organisms. In fact, the nucleus-encoded genes specifying COX II and COX III (Perez-Martinez et al., 2000 , 2001 ; Watanabe and Ohama, 2001 ), and, as reported herein and elsewhere (Funes et al., 2002 ), ATPase 6, have been identified in algal species, including C. reinhardtii.

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